Substances addressing the opioid system are widely used pharmaceuticals. Agonists (narcotic analgesics) are used for the treatment of chronic pain, whereas antagonists are generally effective in the treatment of addictive disorders, including substance abuse (opiate, alcohol, amphetamine) and non-substance, i.e. behavioral addictions such as gaming, gambling and over-eating. The proposed program project will use structural, biophysical, biochemical, and pharmacological approaches to understand ligand binding properties of all opioid receptors (p-, 6, K (MOR, DOR, KOR), and the nociceptin/orphanin FQ peptide receptor (NOP)) and to define the structural basis for molecular recognition and activation. The three overall aims are (1): Understand opioid receptor molecular recognition and functional selectivity using X-ray crystallography to determine structures of ligand-receptor complexes and NMR to understand dynamic behavior. (2) Understand the molecular mechanisms for functional and pharmacological selectivity for the four opioid receptors using computational approaches, and (3) Understand ligand-directed signaling (G- protein-, arrestin-, JNK-dependent) and its relevance in mediating opioid receptor action. Management and administration of the project will be carried out by the Management and Administration Core. Its main responsibilities include (1) Overall management of all project to ensure progress, (2) Prioritization of studies, (3) Assembly of a Scientific Advisory Board, (4) Preparation of required progress reports, (5) Establishment and facilitation of communication routes within the POI as well as with external stakeholders (e.g. SAB, NIH), and (6) Assurance ofthe high quality of studies and results.